BRPI0718059A2 - AMINOMETIL-2-IMIDAZOOS WITH AFFINITY WITH AMINE-ASSOCIATED TRACE RECEIVERS - Google Patents

Description

Descriptive Report of the Invention Patent for "Aminomethyl-2-Imidazoles Affinity to Amino-Associated Trace Receptors".

The present invention relates to the compounds of formula I

R1

/ -K

NNH

Arv> „,

in which

R1 is hydrogen or lower alkyl;

R2 is hydrogen, lower alkyl, lower alkenyl, lower alkyl

replaced by hydroxy,

lower alkyl substituted by halogen;

- (CH2) xS-lower alkyl, - (CH2) x-0-lower alkyl, - (CH2) x-NHC (0) 0-lower alkyl, - (CH2) x-aryl or - (CH2) x-heteroaryl ;

R3 is hydrogen, lower alkyl, lower alkoxy, halogen, hydroxy, lower alkyl substituted by halogen; -0- (CH2) m -aryl, -0- (CH2) m -heteroaryl, - (CR2) m-aryl or

- (CR 2) m -heteroaryl;

R is hydrogen, lower alkyl or hydroxy; Ar is phenyl, pyrimidin-2-yl, pyrimidin-4-yl or pyridin-3-yl; η is 0, 1, or 2; when η is 2, then the two groups R3 may or may not be the same;

χ is 0.1, 2 or 3;

m is 0 or 1; when m is 1, then the two groups R may or may not be the same; and their pharmaceutically active salts, with the exception of the following known compounds: K1 = (1H-18midazol-2-ylmethyl) -phenylamine (CAS 166096-14-6) K1 = (7H-imidazol-2-ylmethyl) ) -phenylamine (CAS 166096-14-6), K2 = (4-fluorophenyl) - (1H-imidazol-2-ylmethyl) -amine (CAS 166096-17-9), K3 = (4-chloro -phenyl) - (7 / - / - imidazol-2-ylmethyl) -amine (CAS 166096-16-8), K4 = (1H-imidazol-2-ylmethyl) - (2-methoxy-phenyl) -amine (CAS 660405-06-1), K5 = (3-chloro-phenyl) - (1H-imidazol-2-ylmethyl) -amine (CAS 660405-04-9), K6 = benzyl- (7H-imidazol-2-ylmethyl) -phenylamine (CAS 371974-08-2), K7 = ethyl- (7H-imidazol-2-ylmethyl) -phenylamine (CAS 35294-97-4) and

K8 = (3,4-dichloro-phenyl) - (1H-imidazol-2-ylmethyl) -amine

(CAS 744972-57-4).

Specific compounds excluded from the scope of the novel compounds of formula I are described, for example, in the references mentioned below or are included in public chemical libraries.

The invention includes all racemic mixtures, all the corresponding enantiomers and / or optical isomers.

Furthermore, all tautomeric forms of the compounds of formula I are also encompassed by the present invention. The compounds of formula I have been found to have a good affinity

trace amine associated receptors (TAARs), especially with respect to TAAR1.

The compounds may be used for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress related disorders, psychotic disorders such as schizophrenia, neurological disorders such as disease. Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, consumption and assimilation disorders. - energy connection, disorders and malfunction of body temperature homeostasis, sleep disorders and circadian rhythm, and cardiovascular disorders. Classic biogenic amines (serotonin, norepinephrine, epinephrine, dopamine, histamine) play important roles as neurotransmitters in the central and peripheral nervous systems [1]. Their synthesis and storage as well as their degradation and resorption after release are strictly regulated. An imbalance in biogenic amine levels is known to be responsible for altered brain function under many pathological conditions [2-5]. A second class of endogenous amine compounds, the so-called trace amines (ATs) significantly overlap with biogenic amines in terms of subcellular structure, metabolism, and location. AT include p-tyramine, β-phenylethylamine, triiptamine and octopamine, and they are present in the mammalian nervous system at generally lower levels than classic biogenic amines [6],

Their dysregulation has been linked to a variety of psychiatric illnesses such as schizophrenia and depression [7] and other conditions such as attention deficit hyperactivity disorder, migraine headache, Parkinson's disease, substance abuse, and there disorders. - mentation [8,9].

For a long time, TA-specific receptors have been hypothesized only on the basis of anatomically separated high affinity AT binding sites in the CNS of humans and other mammals [10, 11]. Consequently, the pharmacological effects of AT have been believed to be mediated through the well known machinery of classical biogenic amines, either by triggering their release, inhibiting their reabsorption or by "cross-reacting" with their receptor systems. [9, 12, 13]. This view has changed significantly with the recent identification of several members of a new GPCR family with trace amine-associated receptors (TAARs) [7, 14]. There are 9 TAAR genes in humans (including 3 pseudo genes) and 16 genes in mice (including 1 pseudo gene). The TAAR genes do not contain introns (with one exception TAAR2 contains 1 intron) and are located next to each other on the same chromosome segment. Phylogenetic relationships of receptor genes, according to a similarity comparison of deep GPRC pharmacophor and pharmacological data, suggest that these receptors form three distinct subfamilies [7, 14]. TAAR1 is the first subclass of four highly conserved TAAR1 genes 4) among humans and rodents. ATs activate TAAR1 via Gas. Deregulation of AT has been shown to contribute to the etiology of various diseases such as depression, psychosis, attention deficit and hyperactivity disorder, substance abuse, Parkinson's disease, migraine headache, eating disorders, metabolic disorders and For this reason, TAAR1 ligands have a high potential regarding the treatment of these diseases.

For this reason, there is widespread interest regarding the increased knowledge about these receptors associated with trace amines. References used:

1 Deutch, A.Y. and Roth, R.H. (1999) Neurotransmitters. In Fundamental Neuroscience (2nd edn) (Zigmond, M.J., Bloom, F.E., Landis, S.C., Roberts, J.L, and Squire, L.R., eds.), Pp. 193-234, Academic Press;

2 Wong, M.L. and Licinio, J. (2001) Research and treatment approaches to depression. Nat. Rev. Neurosci. 2,334-351;

3 Carlsson, A. et al. (2001) Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. Annu Rev. Pharmacoi Toxicol 41, 237-260;

4 Tuite, P. and Riss, J. (2003) Recent developments in the pharmacological treatment of Parkinson's disease. Expert Opin. Investigation Drugs 12, 1335-1352,

Castellanos, F.X. and Tannock, R. (2002) Neuroscience of attention deficit / hyperactivity disorder: the search for endophenotypes. Nat. Rev. Neu- rosci. 3,617-628;

6 Usdin, Earl; Sandler, Merton; Publishers. Psychopharmacology Series, Vol. 1: Trace Amines and the Brain. [Proceedings of a Study Group at the 14th Annual Meeting of the American College of Neuropsychoparmacology, San Juan Puerto Rico] (1976);

7 Lindemann, L. and Hoener, M. (2005) A renaissance in trace amines inspired by a novel GPCR family. Trends in Pharmacol. Know. 26, 274-281;

8 Branchek1 T.A. and Blackbum, T.P. (2003) Map amine receptors as targets for novel therapeuties: Iegend, myth and fact. Curr. Opin. Pharmacol.

3, 90-97;

9 Premont, R.T. et al (2001) Following the trace of elusive amines. Proc. Aí / there /. Acad. Know. U.S.A. 98, 9474-9475;

Mousseau, D.D. and Butterworth, R.F. (1995) A high-affinity [3H] tryptamine binding site in human brain. Prog. Brain Res. 106, 285-291;

11 McCormack1 J.K. et al. (1986) Autoradiographic Iocalization of tryptamine binding sites in the rat and dog central nervous system. J. Neurosci. 6, 94-101;

12 Dyck, L.E. (1989) Release of some endogenous trace amines from striatal rat slices in the presence and absence of a monoamine oxidase inhibitor.

Life I know. 44, 1149-1156;

13 Parker, E.M. and Cubeddu, L.X. (1988) Comparative effects of amphetamine, phenylethylamine and related drugs on dopamine efflux, dopamine uptake and mazindol binding. J. Pharmacol. Exp. Ther. 245, 199-210;

14 Lindemann, L. et al. (2005) Trace amine associated receptors form structurally and functionally distinct subfamilies of novel G protein-coupled receptors. Genomics 85,372 - 385.

The objects of the present invention are the novel compounds of formula I, the manufacture thereof, medicaments based on a compound according to the invention and the production thereof as well as the use of the compounds of formula I for the control or prevention of disorders such as depression, anxiety disorders, bipolar disorders, hyperactivity disorder and attention deficit (ADHD) stress-related disorders, psychotic disorders such as schizophrenia, neurological disorders such as Parkinson's disease, neuro degenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, consumption and energy assimilation disorders, disorders and malfunctioning of body temperature homeostasis, sleep disorders and circadian and distal rhythm cardiovascular sounds.

Indications preferably with the use of the compounds of the

The present invention is depression, psychosis, Parkinson's disease, anxiety and attention deficit hyperactivity disorder (ADHD).

As used herein in this patent application, the term "lower alkyl" denotes a saturated straight or branched chain group containing from 1 to 7 carbon atoms, for example methyl, ethyl, propyl. isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl and the like. Preferably alkyl groups are groups of 1 to 4 carbon atoms.

As used herein, in this patent application, the term "lower alkenyl" denotes a saturated straight or branched chain group containing from 2 to 7 carbon atoms, wherein at least one bond is a double bond. .

As used herein, in this patent application, the term "lower alkoxy" denotes a group in which the alkyl residue is defined above and which is attached through an oxygen atom. In the form used herein, in this patent application, the term "

halogen substituted lower kyl "denotes an alkyl group as defined above in which at least one hydrogen atom is substituted by halogen, for example CF3, CHF2, CH2F, CH2CF3, CH2CH2CF3, CH2CF2CF3 and the like. used herein in this patent application the term "aryl"

indicates an aromatic group selected from phenyl, naphthalen-1-yl or naphthalen-2-yl.

In the form used herein, in this patent application, the term heteroaryl is an aromatic group containing at least one O, N or S ring atom selected from the group consisting of thiophenyl, pyridinyl, pyridine, and the like. Midinyl. benzofuranyl or indolyl.

The term "halogen" indicates chlorine, iodine, fluorine and bromine. The phrase "pharmaceutically acceptable acid addition salts" includes salts with inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, acid succinic acid, tartaric acid, methane sulfonic acid, p-toluene sulfonic acid and the like.

A group of compounds are those of the formula

N NH

in which

R1 is hydrogen or lower alkyl;

R2 is hydrogen, lower alkyl, lower alkenyl, lower alkyl

replaced by hydroxy,

lower alkyl substituted by halogen; - (CH 2) x -S-lower alkyl, - (CH 2) x -O lower alkyl, - (CH 2) x-NHC (O) lower alkyl, - (CH 2) x -aryl or - (CH 2) x heteroaryl;

R3 is hydrogen, lower alkyl, lower alkoxy, halogen, hydroxy, lower alkyl substituted by halogen; -0- (CH2) m -aryl, -0- (CH2) m -heteroaryl, - (CR2) m-aryl or

- (CR 2) m -heteroaryl; R is hydrogen, lower alkyl or hydroxy;

X / X 'are independently CH or N, where XeX' are not simultaneously N;

η is 0, 1 or 2; when η is 2, then the two groups R3 may or may not be the same; χ is Ο, 1,2 or 3;

m is 0 or 1; when m is 1, then the two groups R may or may not be the same;

and their pharmaceutically active salts, with the exception of the following known compounds: (7H-imidazol-2-ylmethyl) -phenylamine, (4-fluorophenyl) - (7H-imidazol-2-ylmethyl) -amine , (4-chloro-phenyl) - (7H-imidazol-2-ylmethyl) -amine, (7 / - / - imidazol-2-ylmethyl) - (2-methoxy-phenyl) -amine, (3-chloro-phenyl ) - (7H-Imidazol-2-ylmethyl) -amine, benzyl - ("H-imidazol-2-ylmethyl) -phenylamine, ethyl (7H-imidazol-2-ylmethyl) -phenylamine and (3 , 4-dichloro-phenyl) - (1H-imidazol-2-ylmethyl) -amine.

Preferred compounds of formula I are those wherein Ar is phenyl. They are especially preferred from this group to those in which R1 is lower alkyl.

These compounds are: (3-chloro-phenyl) - (1H-imidazol-2-ylmethyl) -methyl-amine (4-chloro-phenyl) - (1H-imidazol-2-ylmethyl) -methyl-amine (1 H-imidazol-2-ylmethyl) - (3-methoxy-phenyl) methyl-amine (4-fluorophenyl) - (1H-imidazol-2-ylmethyl) -isopropyl-amine ethyl (3-fluorophenyl) ) - (1 H -imidazol-2-ylmethyl) amine (3-chloro-phenyl) - (1H-imidazol-2-ylmethyl) -isopropyl-amine (3-chloro-phenyl) -ethyl- (1 H- imidazol-2-ylmethyl) amine (2,5-difluoro-phenyl) - (3H-imidazol-4-ylmethyl) -isopropyl-amine (1H-imidazol-2-ylmethyl) -isopropyl-m-tolyl-amine ( 3-benzyloxy-phenyl) - (1H-imidazol-2-ylmethyl) -isopropyl-amine (1H-imidazol-2-ylmethyl) -isopropyl- [3- (pyridin-3-yloxy) -phenyl] -amine (3 -benzyl-phenyl) - (1H-imidazol-2-ylmethyl) -isopropyl-amine biphenyl-3-yl- (1H-imidazol-2-ylmethyl) -isopropyl-amine

[3- (4-Chloro-phenoxy) -phenyl] - (1H-imidazol-2-ylmethyl) -isopropyl-amine Ethyl-HI-imidazol-4-ylmethylHS-phenoxy-phenyl-amine (3-benzyloxy-phenyl) -ethyl- ( 1H-imidazol-2-ylmethyl) -amine or (3,4-dichloro-phenyl) -ethyl- (1H-imidazol-2-ylmethyl) -amine.

Also preferably are compounds in which Ar is phenyl and R2 is - (CH2) x -O-lower alkyl, for example the following compound: (1H-imidazol-2-ylmethyl) - (2-methoxy-ethyl) -phenyl the mine.

Also preferably are compounds in which Ar is phenyl and R2 is hydrogen, for example the following compounds: (1H-imidazol-2-ylmethyl) - (3-phenoxy-phenyl) -amine (3-benzyloxy-phenyl) (1H-Imidazol-2-ylmethyl) -amine (4-chloro-3-methoxy-phenyl) - (1H-imidazol-2-ylmethyl) -amine (3-bromo-phenyl) - (1H-imidazol-2- ylmethyl) -amine (3,4-difluoro-phenyl) - (1H-imidazol-2-ylmethyl) -amine (3-chloro-4-fluoro-phenyl) - (1H-imidazol-2-ylmethyl) -amine K8 = (3,4-dichloro-phenyl) - (1H-imidazol-2-ylmethyl) -amine. A further embodiment of the invention are the compounds of

formula I, wherein Ar is pyrimidin-2-yl, pyrimidin-4-yl or pyridin-3-yl.

The present compounds of formula I and the pharmaceutically acceptable salts thereof may be prepared by methods known in the art, for example, by the processes described below, the processes of which comprise:

(a) reacting a compound of the formula

<RSWAr, NH!

Ar jj

with a compound of the formula

HN ^: N

R1

O ^ m

for a compound of formula R1

/-H

No. .NH

.R2

N

Ar \ 3 (R) n

I

wherein R11 R21 R3 and Ar are as defined above, or (b) by reacting a compound of the formula

R1

ή = \ NyNH

NH

(R) n

II

with a compound of the formula R2-CHO to a compound of the formula

R1

/ = K

NNH

^ N ^ R2 'Arv 3 <R> »1-2

wherein R2 is lower alkyl, lower alkenyl, hydroxy substituted lower alkyl, halogen substituted lower alkyl, - (CH2) xiS-lower alkyl, - (CH2) xi-O-lower alkyl, (CH2) xi-NHC (0 ) O-lower alkyl or (CH 2) x I -heteroaryl and the other substituents are as defined above, or (c) by reacting a compound of the formula

R1

/ = K

NyNH

NH

Al \ 3

(R) n

II

with

ο-

ίο

for a compound of formula R1

/ = K

NvNH Arx

(R3) n] _3

wherein the substituents are as defined above, or

(d) removing a protecting group and compound from the formulas

R1 R1

/ = K / = K

fK, NH N1 / N-PG

N-R2 N'r2

(R) n-PG I will <R) "VIII

for a compound of the formula

R1

/ = K

N / NH

n'r

Ar \ 3 (R) n

I

wherein the substituents are as defined above, or (e) reducing a compound of the formula

R1

H = \

NyNH

<A-r2

Arv> „

VII

for a compound of the formula

R1

/ = K

N-PG

N-R2

Al \ 3

(R) No. VIII

and removing the protecting group for a compound of formula I wherein the substituents are as defined above, or (f) reacting a compound of formula

(R3U. Ρ

N

with a compound of formula PG.

XII

\

No

N—

^ XI

for a compound of the formula

R1

r * = \

XIII

and removing the protecting group for a compound of the formula

1-4

which substituents are as defined above, and

if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.

The compounds of formula I may be prepared according to the process variants described above and the following schemes 1-5. The starting materials are either commercially available, or otherwise known in the chemical literature, or may be prepared according to methods well known in the art. Method 1. Scheme 1

(R3) n-

/ "Air

R

I

NH

H N-

NaCNBH3 ZnCL

or NaBH (OAc) 3 CF3CO2H

(RV

R N-

K

HHy ^ J

Air

The compounds of formula I may be prepared by reduction amination using an aniline of formula II and imidazol-2-carbaldehyde of formula III in the presence of NaCNBH3 or Na-BH (OAc) 3. Method 2

Scheme 2

(R) n \

, NH,

Air

R1

NaBH.

(r3) s

Air'

THE?

1-1

1 ^ λ P1 R \ _ ^ R

, JA ^ K MarMRW I-I ^ l--

(R3) n / VX4 S / + ZnCl2 J (R3) nx ki ^,

Ar ^ N R2-CHO _ ^ 'n \

IV or NaBH (OAc) 3 1-2

1-1 rc i "n u

<RV dCV ^ 1 CF3COOH (RJ) n \ .N

NaBH (OAc) 3 3 HN 2 sfR

1-1 n

which R2 is lower alkyl, lower alkenyl, hydroxy substituted lower alkyl, halogen substituted lower alkyl, - (CH2) x -rS-lower alkyl, - (CH2) xi-O-lower alkyl, (CH2) x-rNHC (0) 0-lower alkyl or (CH2) xI-

heteroaryl.

Scheme 2 describes the preparation of compounds of formulas 1-1. 1-2 or 1-3 by reduction amination followed by derivatization with N. Method 3. Scheme 3

, 1 R HN t-R

R2 HN- ^ Vr m3 \

Air

V)

Scheme 3 describes deprotection of a compound of formula V to a compound of formula I (deprotection is carried out in the usual manner. Compounds of formula V may be prepared according to methods 1 or 2. Method 4. Scheme 4

amide coupling PG

p2 PG reagent R2 N- ^ R1

(KrNH H00cAnJ V ^

In vile vi

PG Ri

^ 2 ") 3R1 BH3QrLiAlH4 ^ JJQ

'' nVaN

The Vll

PG. - ■ - R

Di

(R) n \ A / ^ c.

Ar Y N VIM

Vlll

Starch coupling reagent; 2. Unprotect))

Scheme 4 describes the preparation of a compound of formula I by formation of an amide followed by reduction of amide bonding and removal of the protecting group. Method 5

Scheme 5

R-NH2 IX

PG

OHC ^ iM X

reductive amination

PG

R HN.

N

Xl

PG

2 \ _ D1

R N ^ r

Hn

Xl

(R3) n

THE?"

Xlll

(R3) no.

N

PG

deprotect

(R3) n

Xlll

nJX ^ '

R1

I-4

Amination by reduction; 2. Unprotect))

Scheme 5 describes the preparation of a compound of formula 1-4 (X1 is N) by formation of pyridine compounds by reaction of 4-fluoropyridines to protected aminoethyl imidazoles. Isolation and purification of compounds.

Isolation and purification of the compounds and intermediates described herein in this patent application may be effected if desired by any separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin layer, thick layer chromatography, low- or high-pressure liquid preparation chromatography, or combinations of these procedures. Specific illustrations of suitable separation and isolation procedure may be given by reference to the following preparations and examples herein in this patent application. However other equivalent separation and isolation procedures can of course also be used. Racemic mixtures of chiral compounds of formula I may be separated using chiral HPLC. Salts of compounds of formula I.

The compounds of formula I are basic and may be converted to a corresponding acid addition salt. Conversion is accomplished by treatment with at least a stoichiometric amount of an appropriate acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acid. acetic, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethane acid sulfonic acid, p-toluene sulfonic acid, salicylic acid and the like. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and the acid is added in a similar solvent. The temperature is maintained between 0 ° C and 50 ° C. The resulting salt precipitates spontaneously or may be removed from solution with a less polar solvent.

The acid addition salts of the basic compounds of formula I may be converted to the corresponding free bases by treatment with at least one stoichiometric equivalent of a suitable TAC base such as sodium or potassium hydroxide, potassium carbonate. sodium, baking soda, ammonia and the like.

The compounds of formula I and their pharmaceutically usable acid addition salts have valuable pharmacological properties. Specifically, it has been found that the compounds of the present invention have a good affinity for trace amine associated receptors (TAARs), especially TAAR1.

The compounds were investigated according to the tests provided hereinafter in this patent application. Materials and methods

Construction of TAAR expression plasmids and stably transfected cell lines.

For the construction of expression plasmids the human, rat and mouse TAAAR 1 coding sequences were amplified from genomic DNA, essentially as described by Lindemannet al. [14] The Expand High Fidelity PCR System (Roche Diagnostics) was used with 1.5 mM MG2 + and the purified PCR products were cloned into the pCR2.1-TOPO cloning vector (Invitrogen) following the manufacturer's instructions. PCR products were subcloned into the p1-RESneo2 vector (BD Clontech, Palo Alto, California), and expression vectors were checked for sequence before being introduced into the cell lines.

HEK293 cells (ATCC # CRL-1573) were cultured essentially as described in Lindemann et al. (2005). For the generation of stably transfected cell lines, HEK293 cells were transfected with plRESneo2 expression plasmids containing the TAAR coding sequences (described above) with Lipofectamine 2000 (Invitrogen) according to the manufacturer's instructions. and after transfection the culture medium was supplemented with mg / ml G418 (Sigma, Buchs, Switzerland). After a culture period of about 10 days the clones were isolated, expanded and tested for amine responsiveness (all compounds were purchased from Sigma) with the cAMP Biotrak Enzyme (EIA) System immunoassay ( Amersham) following EIA non-acetylation procedures provided by the manufacturer. The monoclonal cell lines exhibiting an EC50 over a 15-pass culture period were used for all studies that followed.

Membrane preparation and radioligand binding.

The confluent cells were rinsed with phosphate-buffered cold saline without Ca 2+ and Mg 2+ containing 10 mM EDTAQ and pelleted by centrifugation at 1000 rpm for 5 minutes at 4 ° C. The pellet was then washed twice with phosphate buffered ice saline and the cell pellet was immediately frozen by immersion in liquid nitrogen and stored until used at -80 ° C. The cell pellet was then suspended in 20 ml HEPES-NaOH (20 mM), pH 7.4 containing 10 mM EDTA1 and homogenized with a Polytron (PT 3000, Kinematica) at 10,000 rpm for 10 s. The homogenate was centrifuged at 48,000 g for 30 minutes at 4 ° C and the pellet was resuspended in 20 ml HEPES-NaOH (20 mM), pH 7.4 containing 0.1 mM EDTA (buffer A), homogenized with a Polytron at 10,000 rpm for 10 s. The homogenate was then centrifuged at 48,000 χ g for 30 minutes at 4 ° C and the pellet was resuspended in 20 ml of buffer A, and homogenized with a Polytron at 10,000 rpm for 10 s. Protein concentration was determined by the Pierce method (Rockford, II). The homogenate was then centrifuged at 48,000 χ g for 10 minutes at 4 ° C, resuspended in HEPES-NaOH (20 mM), pH 7.0 including MgCl 2 (10 mM) g protein per ml and (2 mM) (buffer B) at 200 ° C homogenized with a Polytron at 10,000 rpm for 10 seconds.

Binding analysis was performed at 4 ° C in a final volume of 1 ml, and with an incubation time of 30 minutes. [3H] -rac-2- (1,2,3,4-tetrahydro-1-naphthyl) -2-imidazoline radio ligand was used at a concentration equal to the calculated Ka value of 60 nM to give a binding around 0.1% of the total concentration of the added ligand and a specific binding representing approximately 70 - 80% of the total binding. Nonspecific binding was defined as the amount of [3 H] -rac-2- (1,2,3,4-tetrahydro-1-naphthyl) -2-imidazoline bound in the presence of the appropriate unlabelled ligand (10 μ.).

Competing ligands were tested over a wide concentration range (10 pM - 30 (M), the final concentration of dimethyl sulfoxide in the analysis was 2% and it did not affect radioligand binding. Each experiment was performed All incubations were terminated by rapid filtration through UniFilter-96 plates (Packard Instrument Company) and GP / C glass filter, pre-soaked for at least 2 hours in 0.3% polyethyleneimine and using a Filtermate 96 Cell Harvester (Packard Instrument Company) .The tubes and filters were then washed 3 times with 1 ml aliquots of cold Buffer B. The filters were not dried and soaked in Ultima gold (45 μΙ / well, Packard Instrument Company) and bound radioactivity was counted by a TopCount Microplate Scintillation Counter (Packard Instrument Company).

The compounds preferably exhibited a mouse Ki value (μΜ) in TAAR1 in the range of 0.002 to 0.100 as shown in the table.

Below Example Ki (μΜ) mouse Example Ki 2 0.030 46 0.077 0.081 51 0.082 6 0.073 61 0.0261 0.094 62 0.0028 12 0.051 64 0.0259 0.050 65 0.0111 21 0.082 66 0.0263 0.036 68 0.0331 37 0.065 71 0.0995 39 0.089 73 0.0708 41 0.021 74 0.0839 43 0.025 K8 0.055 45 0.002

The compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I may be used as medicaments, for example in the form of pharmaceutical preparations. Pharmaceutical preparations may be administered orally, for example in the form of tablets, coated tablets, tablets, hard and soft gelatin capsules, solutions, emulsions or suspensions. Administration, however, may also be rectally, such as in the form of suppositories, parenterally, for example in the form of solutions for injection.

The compounds of formula I may be processed with pharmaceutically inert, inorganic or organic vehicles for the manufacture of pharmaceutical preparations. Lactose, maize starch or derivatives thereof, talc, stearic acids or salts thereof and the like may be used, for example, as tablet carriers, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-liquid and solid polyols and the like. Depending on the nature of the active substance, no carrier however is usually required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable vehicles for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

Pharmaceutical preparations may furthermore contain preservatives, solubilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for osmotic pressure variation, buffers, masking agents or antioxidants. They may also contain other substances of therapeutic value.

Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as well as a process for producing them, comprising taking one or more compounds of formula I and / or pharmaceutically acceptable acid addition salts, and if one or more therapeutically valuable substances is desired in a dosage administration form together with one or more therapeutically inert carriers.

Most preferred indications according to the present invention are those which include disorders of the central nervous system, for example, the treatment or prevention of schizophrenia, depression, cognitive impairment and Alzheimer's disease.

The dosage may vary within broad limits and will, of course, have to be adjusted with respect to the individual's needs in the particular case. For oral administration, the adult dosage may range from about 0.01 mg to about 1000 mg per day of a compound of general formula I or the corresponding amount of a pharmaceutically acceptable salt of the compound. same. The daily dosage may be administered as a single dose or in divided doses and, moreover, the upper limit may also be exceeded when considered as indicated. Tablet Formation (Wet Granulation)

Item Ingredients mq / tablet 5 mg 25 mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500 2. Anhydrous lactose DTG 125 105 30 150 3. Sta-Rx 1500 6 6 6 30 4. Micro crystalline cellulose 30 30 30 150 5. Magnesium Stearate 1 1 1 1 Total 167 167 167 831

Manufacturing Procedure

1. Mix items 1, 2, 3 and 4 and granulate with purified water.

2. Dry the granules at 50 ° C.

3. Pass the granules through suitable grinding equipment.

4. Add item 5 and mixtures for 3 minutes; compress in a suitable press.

Capsule Formation.

Item Ingredients mq / capsule 5 mg 25 mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500 2. Water lactose 159 123 148 - 3. Corn starch 25 35 40 70 4. Talc 10 15 10 25 5. Stearate of Magnesium 1 2 2 5 Total 200 200 300 600

Manufacturing Procedure.

1. Mix items 1, 2 and 3 in a suitable mixed for 30 minutes.

2. Add items 4 and 5 and mix for 3 minutes

3. Fill into a suitable capsule. Experimental.

The following examples illustrate the invention but are not intended to limit the scope thereof. Example 1. Example 1

(1H-1midazol-2-ylmethyl) -isopropyl-phenylamine

r = \

a) (1H-1midazol-2-ylmethyl) -phenylamine

To a solution of aniline (0.50 g, 5.37 mmol) in methanol (7 mL) was added imidazole-2-carboxyaldehyde (0.62 g, 6.45 mmol). After stirring the mixture overnight at room temperature sodium borohydride (0.305 g, 8.05 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. Then water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated. The residue was purified by crystallization (ethyl acetate) to give the white solid (0 to 71 g, 76%); MS (ISP): 174a1 ((M + H) +).

b) (1H-1midazol-2-ylmethylVisopropyl-phenyl amine

To a solution of (1H-imidazol-2-ylmethyl) -phenylamine (0.71 g, 4.1 mmol) in 1,2-dichloroethane (10 mL) was successively added 2-methoxypropane (0.5 mL, 5.3 mmol), trifluoroacetic acid (0.47 ml, 6.1 mmol) and sodium triacetoxyborohydride (1.3 g, 6.1 mmol). After stirring the mixture overnight at room temperature, water and ethyl acetate were added. After extraction of the aqueous phase twice with ethyl acetate the combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by column chromatography (SiO 2, heptane / ethyl acetate = 1: 1) to give a white solid (0.335 mg, 38%); MS (ISP): 216.2 ((M + H) +). Example 2

(3-chloro-phenyl) - (1H-imidazol-2-ylmethyl) -methylamine

/ = \

To a solution of 3-chloro-N-methylaniline (0.283 g, 2 mmol) in 1,2-dichloroethane (10 ml) was added molecular leggings (2 g, 0.4 nM size) and imidazole-2-carboxyaldehyde ( 0.288 g, 3 mmol). After stirring the mixture for 5 minutes at room temperature sodium triacetoxyborohydride (0.848 g, 4 mmol) and acetic acid (5 drops) were added. The reaction mixture was stirred at room temperature overnight. During work up dichloromethane (50 mL) and 1 M sodium bicarbonate solution (30 mL) were added and the mixture was shaken. The organic layer was separated, dried over magnesium sulfate and evaporated. The residue was purified using flash chromatography (column: Isolute® FIash-NH2 (Separtis); eluent: ethyl acetate / methanol = 95: 5) to give a white solid (0.13g, 29%); MS (ISP): 222.1 ((M + H) +). Example 3

2 - [(1H-1midazol-2-ylmethyl) -phenyl-aminol-ethane

The title compound, MS (ISP): 218.2 ((M + H) + ") was obtained in comparable yield as analogous to the procedure described for Example 2 using N- (2-hydroxyethyl) -aniline in place of 3-chloro-N-methylaniline Example 4

(1 H -imidazol-2-ylmethylH4-methoxy-phenylmethylamine

/ = \

The title compound, MS (E1): 218.4 ((M + ") was obtained on a comparable yield analogous to the procedure described for Example 2 using N-methylmethoxyaniline in place of 3-chloro. -N-methylaniline Example 5

(4-Chloro-phenyl-1H-imidazol-2-ylmethyl) -methylamine

The title compound, MS (ISP): 222.1 ((M + H) +) was obtained in comparable yield as in the procedure described for Example 2 using N-methyl chloroaniline instead. 3-chloro-N-methylaniline. Example 6

(1 H-1midazol-2-ylmethylH3-methoxy-phenylmethylamine

The

a) 1-Benzyl-1H-imidazole-2-carboxylic acid (3-methoxyphenyl) methyl

amide

N-Methyl-3-methoxyaniline (0.302 g, 2.0 mmol) was dissolved in acetonitrile (10 mL). Then 1-benzyl-2-imidazolecarboxylic acid (0.302 g, 2.2 mmol), N-ethyldiiso, propylamine (0.775 g, 6 mmol), 2- (1H-benzotriazol-1-yl) -1 tetrafluorborate, 1,3,3-tetramethyluronium (TBTU; 1.0 g, 3.1 mmol) and for complete dissolution 2 ml of dimethylformamide were added. The reaction mixture was stirred overnight at room temperature. To work the acetonitrile was evaporated under vacuum, a sodium bicarbonate solution was added and the mixture was extracted twice with dichloromethane. The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified using chromatography (SiO 2; eluent: dichloromethane / methanol = 97: 3) to give a light yellow oil (0.485g, 75%); MS (ISP): 322.2 ((M + H) +).

b) (1-Benzyl-1H-imidazol-2-ylmethylH3-methoxy-phenyl V-methyl-amine

A solution of 1-benzyl-1H-imidazole-2-carboxylic acid (3-methoxyphenyl) methyl amide (0.20 g, 0.64 mmol) was dissolved in tetrahydrofuran (5 ml). Then the borane and tetrahydrofuran solution (3.6 mL, 1 M, 3.6 mmol) was added at 0 ° C and the reaction mixture was heated for 4 hours. Hydrochloric acid (1M) was added to the work until gas evolution was stopped. Then the organic solvent was evaporated, more hydrochloric acid (3 ml, 1M) was added and the mixture was heated to 100 ° C for 1 hour. After cooling, an ammonium hydroxide solution (25%) was added until the basic pH focused and the mixture was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (SiO 2: heptane / ethyl acetate = 1: 1) to give a light yellow oil (0.086 g, 44%); MS (ISP): 308.1 ((M + H) +).

c) (1H-1midazol-2-ylmethylH3-methoxy-phenylmethylamine

(1-Benzyl-1H-imidazol-2-ylmethyl) - (3-methoxy-phenyl) -methylamine (0.077 g, 0.25 mmol) was dissolved in ethanol (5 mL), acetic acid (0.075 g, 1.25 mmol) palladium on charcoal (15 mg, 10% Pd) was added and the mixture was hydrogenated at 60 ° C for 90 minutes. The catalyst was removed by filtration using Celite. To obtain the free base (removal of acetic acid) the solution was placed on an SCX column (0.5 g of Varian, sulfonic acid modified silica gel). After washing the SCX column with methanol column (1 ml, discarded) the product was released from the column by washing with ammonia in methanol (2 ml, 1 M). The solvent was evaporated and the residue was purified using column filtration (SiO 2; dichloromethane / methanol = 95: 5) to give an undefined white solid (0.04 g, 74%); MS (ISP): 218.0 ((M + H) +). Example 7

Isopropyl- (4-methyl-1H-imidazol-2-ylmethyl) -phenylamine.

The title compound, MS (ISP): 230.1 ((M + H) +) was obtained in comparable yield as analogous to the procedure described for Example 2 using isopropyl phenyl amine instead of 3-chloro-N -methylaniline and 4-methyl-imidazole-2-carboxyaldehyde in place of imidazole-2-carboxyaldehyde. Example 8

(3-Fluoro-phenylH 1 H -imidazol-2-ylmethyl) -isopropylamine

The title compound, MS (ISP): 234.3 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 1 using 3-fluoraniline in place of aniline in step a). Example 9

(2-Fluorophenyl) - (1H-imidazol-2-ylmethyl) -isopropylamine

a) 1-Benzyl-1H-imidazole-2-carboxylic acid (2-fluorophenyl) isopropyl amide

A mixture of 1-benzyl-2-imidazole carboxylic acid (0.624 g, 3.0 mmol) and dichloromethylene dimethyliminium chloride (0.487 g, 3.0 mmol) in dichloromethane (15 mL) was stirred at room temperature for 2 hours . Then N-isopropyl-2-fluoroaniline (0.306 g, 2.0 mmol) and sodium bicarbonate (0.840 g, 10 mmol) were added and stirring was continued overnight. For the operation water was added and the mixture was

betrayed twice with dichloromethane. The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by chromatography (S1O2; eluent: heptane / ethyl acetate = 2: 1) to give a colorless oil (0.268 g, 40%); MS (ISP): 338.3 ((M + H) +).

b) (2-Fluorophenyl) - (1H-imidazol-2-ylmethyl) -isopropylamine

The title compound, MS (ISP): 234.1 ((M + H) +) was obtained from

a comparable yield analogous to the procedure described for Example 6 (b) and (c) using 1-benzyl-1H-imidazole-2-carboxylic acid (2-fluoro-phenyl) -isopropyl-amide in place of 1- benzyl-1H-imidazole-2-carboxylic acid (3-methoxyphenyl) methyl amide in step b).

Example 10

(4-fluorophenyl) - (1H-imidazol-2-ylmethyl) -isopropylamine

The title compound, MS (ISP): 234.0 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 1 using 4-fluoraniline in place of aniline in step a). Example 11

(1 H -imidazol-2-ylmethyl) - (2-isopropyl-6-methyl-phenyl) -amine

/ = X

To a solution of 2-isopropyl-6-methyl aniline (1.49 g, 10 mmol)

In methanol (10 ml) was added imidazole-2-carboxyaldehyde (0.96 g, 10 mmol). After stirring the mixture overnight at 60 ° C Sodium borohydride (0.567 g, 15 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. Then water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated. The residue was purified by chromatography (column: Isolute® FIash-NH2 (Separtis); eluent: heptane / ethyl acetate = 1: 1) to give a white solid (1a29g, 56%); MS (ISP): 230.1. Example 12

Ethyl- (3-fluorophenyl) - (1H-imidazol-2-ylmethyl) -amine

a) (1 H -midazol-2-ylmethyl) - (3-fluoro-phenyl) -amine

To a solution of 3-fluoraniline (0.33 g, 3.0 mmol) in methanol (7 mL) was added imidazole-2-carboxyaldehyde (0.29 g, 3.0 mmol) and the mixture was stirred overnight. the other at 60 ° C. After cooling sodium borohydride (0.17 g, 4.5 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. Then water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated. The residue was purified by chromatography (SiO 2, ethyl acetate) to give light yellow solid (0.315 g, 55%); MS (ISP): 192.1 ((M + H) +). b) Ethyl- (3-fluoro-phenyl- (1H-imidazol-2-ylmethyl) -amine

(1H-1midazol-2-ylmethyl) - (3-fluoro-phenyl) -amine (0.19 g, 1 mmol) was dissolved in methanol (15 mL). Then acetaldehyde (0.28 ml, 5 mmol), zinc chloride (0.55 g, 4 mmol) and sodium cyanoboroidrate (0.31 g, 5 mmol) were added and the reaction mixture was allowed to stir at room temperature. 40 ° C overnight. After cooling, the reaction mixture was poured into ammonium chloride / ice and extracted with ethyl acetate (2 x 50 ml). The organic layer was dried over magnesium sulfate and evaporated. The residue was purified using flash chromatography (S1O2; eluent: heptane / ethyl acetate = 90:10) to give undefined white solid (0.118 g, 54%); MS (ISP): 220.2 ((M + H) +). Example 13

(2-Chloro-phenylH1H-imidazol-2-ylmethyl) -amine

The title compound, MS (ISP): 208.1 ((M + H) +) was obtained in comparable yield as analogous to the procedure described for Example 11 using 2-chloroaniline in place of 2-isopropyl-6. methyl aniline. Example 14

(2-Chloro-phenyl) - (1H-imidazol-2-ylmethyl) -isopropyl-amine The title compound, MS (ISP): 250.1 ((M + H) +) was obtained in comparable yield as the procedure described. for Example 1 using 2-chloroaniline in place of aniline in step a). Example 15

(3-chloro-phenyl) - (1H-imidazol-2-ylmethyl) -isopropyl-amine

/ = \

The title compound, MS (ISP): 250.3 ((M + H) +) was obtained on a comparable yield analogous to the procedure described for Example 1 using 3-chloroaniline in place of aniline in step a) . Example 16

(4-chloro-phenyl) - (1H-imidazol-2-ylmethyl-isopropyl-amine

The title compound, MS (ISP): 250.1 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 1 using 4-chloroaniline in place of aniline in step a). Example 17

(1 H -imidazol-2-ylmethyl-isopropyl- (2-methoxy-phenyl) -amine

The title compound, MS (ISP): 250.1 ((M + H) +) was obtained at a comparable yield analogous to the procedure described for Example 1 using 2-methoxyaniline in place of aniline in step a) . Example 18

(1H-Imidazol-2-ylmethylH3-methylsulfanyl-propyl-Menyl) -amine

NH

The title compound, MS (ISP): 262.1 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 12 with aniline in place of 3-fluoraniline in step a) and 3- (methylthio) propionaldehyde in place of acetaldehyde in step b). Example 19

(1H-imidazol-2-ylmethyl) -isobutyl-phenyl-amine

The title compound, MS (ISP): 230.3 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 12 using aniline instead of 3-fluoraniline in step a) and isobutyraldehyde in place of acetaldehyde in step b). Example 20

(1H-Imidazol-2-ylmethyl) - (3-methyl-but-2-enylMenyl-amine; 1: 1 mixture with (1H-imidazol-2-ylmethylH-3-methyl-butyl) -phenyl-amine

ΓΛ

The title compound, MS (ISP): 242.1; 244.4 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 12 using aniline in place of 3-fluoraniline in step a) and 3-methylcrotonaldehyde in place of acetaldehyde in step b). Example 21

(1 H-1midazol-2-ylmethyl) - (2-methoxyethylHenylamine

The title compound, MS (ISP): 232.3 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 12 using aniline in place of 3-fluoraniline in step a) and methoxyacetaldehyde in place of acetaldehyde in step b). Example 22

(1H-Imidazol-2-ylmethylHenyl- (3,3,3-trifluoropropyl) -amine

The title compound, MS (ISP): 270.4 ((M + H) +) was obtained analogous to the procedure described for Example 12 using aniline in place of 3-fluoraniline in step a) and 3, 3,3-trifluoropropionaldehyde in the acetaldehyde location in step b). Example 23

{2 - [(1H-Imidazol-2-ylmethyl) -phenyl-amino] -ethyl} -carbamic acid tert-butyl ester

N

Y

The title compound, MS (ISP): 317.4 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 12 using aniline in place of 3-fluoraniline in step a ) and tert-butyl carbamate N- (2-oxoethyl) in place of acetaldehyde in step b). Example 24

(1 H -imidazol-2-ylmethyl) phenyl-thiophen-3-ylmethylamine

, NH

The title compound, MS (ISP): 270.3 ((M + H) +) was obtained from a

comparable yield analogous to the procedure described for Example 12 using aniline in place of 3-fluoraniline in step a) and 3-thiophene carboxyaldehyde in place of acetaldehyde in step b). Example 25

(1 H -imidazol-2-ylmethyl) - (3-methoxy-phenyl) -amine

The title compound, MS (ISP): 203.9 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 11 using 3-methoxyaniline in place of 2-isopropyl-6-methyl. -aniline. Example 26

(2-Fluorophenyl) - (1H-imidazol-2-ylmethyl) -amine

The title compound, MS (ISP): 192.0 ((M + H) +) was obtained in comparable yield as analogous to the procedure described for Example 11 using 2-fluoraniline in place of 2-isopropyl-6-methyl. -aniline. Example 27

Ethyl- (1H-imidazol-2-ylmethyl) - (3-methoxy-phenyl) -amine

The title compound, MS (ISP): 231.9 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 12 with the use of 3-methoxyaniline in place of 3-fluoraniline in step a). Example 28

Ethyl- (2-fluoro-phenylH1H-imidazol-2-ylmethyl) -amine

The title compound, MS (ISP): 220.1 ((M + H) +) was obtained in comparable yield as analogous to the procedure described for Example 12 using 2-fluoraniline in place of 3-fluoraniline in the step a). Example 29

Ethyl- (4-fluoro-phenylH1H-imidazol-2-ylmethyl) -amine

The title compound, MS (ISP): 220.2 ((M + H) +) was obtained in comparable yield as analogous to the procedure described for Example 12 using 4-fluoraniline in place of 3-fluoraniline in step a). Example 30

(3-chloro-phenyl) -ethyl- (1H-imidazol-2-ylmethyl) -amine

The title compound, MS (ISP): 235.9 ((M + H) +) was obtained from a

comparable yield analogous to the procedure described for Example 12 using 3-chloroaniline in place of 3-fluoraniline in step a). Example 31

(1H-imidazol-2-ylmethylH2-methoxy-phenyl) -methylamine

The title compound, MS (ISP): 218.4 ((M + H) +) was obtained in comparable yield as analogous to the procedure described for Example 9 using 2-methoxy-N-methylaniline in place of N-isopropyl. Fluoraniline in step a).

Example 32

(1 H -imidazol-2-ylmethyl) methylphenylamine

The title compound, MS (ISP): 188.3 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 9 using N-methylaniline in place of N-isopropyl-2-fluoraniline. in step a). Example 33

(4-FluorophenylH1H-imidazol-2-ylmethyl) methylamine

The title compound, MS (ISP): 206.1 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 12 using 4-fluoraniline in place of 3-fluoraniline in step a) and formaldehyde in place of acetaldehyde in step b).

Example 34

(6-Chloro-pyridin-3-yl) -ethyl- (1H-imidazol-2-ylmethyl) -amine

The title compound, MS (ISP): 208.6; 210.9 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 12 using 5-amino-2-chloropyridine in place of 3-fluoraniline in step a). Example 35

(1H-Imidazol-2-ylmethyl) -isopropyl- (3-methoxy-phenyl) -amine The title compound, MS (ISP): 246.3 ((M + H) +) was obtained in analogous comparable yield. to the procedure described for Example 1 using 3-methoxyaniline in place of aniline in step a). Example 36

(1H-Imidazol-2-ylmethyl) -isopropyl- (3-trifluoromethoxy-phenyl) -amine

/ = \

ia dxv

The title compound, MS (ISP): 300.1 ((M + H) +) was obtained analogous to the procedure described for Example 1 using 3-trifluoromethoxy aniline in place of aniline in step a) . Example 37

(2,5-Difluoro-phenylH3H-imidazol-4-ylmethyl) -isopropylamine

r = \

The title compound, MS (ISP): 284.2; 286.1 ((M + H) +) was obtained analogous to the procedure described for Example 1 using 3,5-dichloroaniline in anugin anugin in step a). Example 38

(3-chloro-5-fluoro-phenyl) - (1H-imidazol-2-ylmethyl) -isopropyl-amine

/ = \

The title compound, MS (ISP): 268.2 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 1 using 3-chloro-5-fluoroaniline in place of aniline. in step a). Example 39

(1H-imidazol-2-ylmethyl) -isopropyl-m-tolylamine

f = \

The title compound, MS (ISP): 230.3 ((M + H) +) was obtained at a comparable yield analogous to the procedure described for Example 1 with the use of 3-methylaniline in anugin in step a. ). Example 40

(4-Fluoro-3-methoxy-phenyl) - (1H-imidazol-2-ylmethyl) -isopropyl-amine

Γ = λ

The title compound, MS (ISP): 264.0 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 1 using 4-fluoro-3-methoxyaniline in place of aniline. in step a). Example 41

(3-benzyloxy-phenyl) - (1H-imidazol-2-ylmethyl) -isopropylamine

The title compound, MS (ISP): 322.3 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 1 using 3-benzyloxyaniline in place of aniline in step a) . Example 42

(3-chloro-5-trifluoromethyl-phenyl) - (1H-imidazol-2-ylmethyl) -isopropyl-amine

The title compound, MS (ISP): 318.1 ((M + H) +) was obtained in comparable yield as analogous to the procedure described for Example 1 using 3-chloro-5-trifluoromethyl aniline instead. of aniline in step a).

Example 43

(1H-imidazol-2-ylmethyl) -isopropyl- [3- (pyridin-3-yloxy) -phenyl-amine

/ = \

The title compound, MS (ISP): 308.4 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 1 using 3- (pyridin-3-yloxy) -phenyl -amine in place of aniline in step a).

Example 44

(1H-Imidazol-2-ylmethyl) -isopropyl- (3-phenoxy-phenyl) -amine-phenylamine

The title compound, MS (ISP): 309.3 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 1 using 3-phenoxy aniline in place of aniline in step The). Example 45

(3-benzyl-phenyl) - (1H-imidazol-2-ylmethyl) -isopropyl-amine

The title compound, MS (ISP): 306.5 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 1 using 3-benzylaniline in place of aniline in step a) . Example 46

Biphenyl-3-yl- (1H-imidazol-2-ylmethyl) -isopropylamine

The title compound, MS (ISP): 292.3 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 1 with the use of biphenyl-3-ylamine in place of aniline in step The). Example 47

Biphenyl-3-yl- (1H-imidazol-2-ylmethyl) -isopropylamine

The title compound, MS (ISP): 308.5 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 1 using 4-phenoxy aniline in place of aniline in step The). Example 48

4- (3'-dichloro-phenoxy) -phenyl1- (1H-imidazol-2-ylmethyl) -isopropyl-amine

Cl

The title compound, MS (ISP): 376.1; 378.2 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 1 using 4- (3 ', 4'-dichlorophenoxy) aniline in place of the anine in step a) . Example 49

(1 H -imidazol-2-ylmethyl-isopropyl-4- (4-trifluoromethyl-phenoxy) -phenyl-1-amine

The title compound, MS (ISP): 376.2 ((M + H) +) was obtained in comparable yield as analogous to the procedure described for Example 1 using 4- (4-trifluoromethyl-phenoxy) -aniline instead. of aniline in step a). Example 50

(1H-Imidazol-2-ylmethyl) -isopropyl-R4- (4-methoxy-phenoxy) -phenyl-1-amine

The title compound, MS (ISP): 338.2 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 1 using 4- (4-methoxy-phenoxy) -aniline in place of aniline in step a).

Example 51

[3- (4-Chloro-phenoxy) -phenyl1- (1H-imidazol-2-ylmethyl-isopropyl-amine

Cl

The title compound, MS (ISP): 342.1; 344.1 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 1 using 4- (4-chloro-phenoxy) -aniline in place of aniline in step a).

Example 52

(2,6-Difluoro-pyridin-4-yn-ethyl- (1H-imidazol-2-ylmetin-amine)

Ethyl-n- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazol-2-ylmethyl-1-amine

To a saturated solution of ethylamine in methanol (3 ml) was added 1- (2-trimethylsilyl) ethoxymethyl-2-imidazole carboxaldehyde (0.2 g, 0.88 mmol) and the mixture was stirred for 1 hour. Sodium borohydride (0.05 g, 1.3 mmol) was added and the mixture was stirred overnight at 50 ° C. Water was added and the solution was extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by scintillation chromatography (SiO 2: ethyl acetate / methanol = 9: 1) to give a yellow oil (0.176 g, 78%); MS (ISP): 256.0 ((M + H) +). b) (2,6-Difluoro-pyridin-4-yl) ethyl- (1H-

A mixture of ethyl [1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazol-2-ylmethyl] -amine (0.1 g, 0.39 mmol) and 2,4,6-trifluoropyridine (0.2 g; 1.5 mmol) was heated in a sealed flask in a microwave oven for 1.5 h at 170 ° C. Then water and dichloromethane were added and the organic layer was separated, dried over magnesium sulfate and evaporated. To the residue was added a solution of tetrabutyl ammonium fluoride in tetrahydrofuran (1M, 1 mL, 1 mmol) and the mixture was stirred overnight. The solvent was evaporated and the residue was purified by scintillation chromatography (column: Isolart® FIash-NH2 from Separtis; eluent: hepta / ethyl acetate = 1: 1) to give a white solid (0 ° C). 01 g, 10%); MS (ISP): 239.0 ((M + H) +). Example 53

(3-f (1H-1midazol-2-ylmethyl) -isopropyl-amino-1-phenyl-phenyl-methanol

The title compound, MS (ISP): 322.4 ((M + H) +) was obtained from a

comparable yield analogous to the procedure described for Example 1 using 3-aminobenzofernone in place of aniline in step a). Example 54

3- (1H-1midazol-2-ylmethyl-isopropyl-aminol-phenol

3-Benzyloxy-phenyl) - (3H-imidazol-2-ylmethyl) -isopropyl-amine (0.285 g,

0.89 mmol) was dissolved in ethanol (5 mL), palladium on charcoal (30 mg, 10% Pd) was added, and the mixture was hydrogenated for 5 hours at room temperature. The catalyst was removed by filtration and the solvent was evaporated. The residue was purified by scintillation chromatography (column: Separtis Isolute® FIash-NH2; eluent: ethyl acetate) to give the white foam (0.162 g, 79%); MS (ISP): 232.1 ((M + H) +). Example 55

(1H-1midazol-2-ylmethyl) -isopropyl-β- (pyridin-4-yloxy) -phenyl-1-amine

The title compound, MS (ISP): 309.3 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 1 using 3- (pyridin-4-yloxy) -phenyl -amine in place of aniline in step a).

Example 56

(1H-Imidazol-2-ylmethyl) -isopropyl- (3-pyrimidin-5-yl-pheninamine)

The title compound, MS (ISP): 294.0 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 1 using (3-pyrimidin-5-yl-phenyl) -amine in place of aniline in step a). Example 57

Ethyl- (1H -imidazol-2-ylmethyl) - (4-methoxy-pyrimidin-2-yl) -amine

The title compound, MS (ISP): 234.1 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 52 using 2-chloro-4-methoxypyrimidine in place of 2 , 4,6-trifluoropyridine in step b). Example 58

(2-Benzyl-6-chloro-pyrimidin-4-yl) -ethyl- (1H-imidazol-2-ylmethyl) -amine

The title compound, MS (ISP): 328.2 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 52 using 2-benzyl-4,6-dichloropyrimidine instead. of 2,4,6-trifluorpyridine in step b). Example 59

(2-Benzyl-pyrimidin-4-yl) -ethyl- (1H-imidazol-2-ylmethyl) -amine

(2-Benzyl-6-chloro-pyrimidin-4-yl) -ethyl- (1H-imidazol-2-ylmethyl) -amine (0.164 g, 0.5 mmol) was dissolved in methanol (5 mL), ammonium formate (0.315 0.5 mmol) and palladium on charcoal (0.164 g,

10

15

20

10% Pd) and the mixture was refluxed for one hour. After cooling the catalyst was filtered off and the solvent was evaporated. The residue was purified by scintillation chromatography (column: Separtis Isolute® Flash-NH2; eluent: ethyl acetate / methanol = 95: 5) to give a white solid (0 to 100 g, 68%); MS (ISP): 294a4 ((M + H) +). Example 60

(3,4-Dichloro-phenylH1H-imidazol-2-ylmethyl) -isopropyl-amine

a) (3,4-Dichloro-phenyl) -isopropyl-amine

3,4-Dichloroaniline (5.0 g, 30.86 mmol) was dissolved in methanol (150 mL). Then acetone (22.7 ml, 308.6 mmol), zinc chloride (12.62 g, 92.58 mmol) and sodium cyano borohydride (7.76 g, 123.4 mmol) were added. and the reaction mixture was allowed to stir at 40 ° C overnight. After cooling, the reaction mixture was poured into ammonium chloride / ice and extracted with ethyl acetate (2 x 200 ml). The organic layer was dried over magnesium sulfate and evaporated. The residue was purified using scintillation chromatography (SiO 2; eluent: heptane / ethyl acetate = 95: 5) to give an undefined white solid (5.03 g, 79.9%); MS (ISP): 205.1 ([37 Cl M + Hf), 203.1 ([35 Cl M + H] +).

b) (3,4-Dichloro-phenylH1 H -imidazol-2-ylmethyl) -isopropyl-amine

(3,4-Dichloro-phenyl) -isopropylamine (0.30 g, 1.47 mmol) was dissolved in methanol (10 mL). Then imidazole-2-carboxaldehyde (0.22 g, 2.20 mmol), zinc chloride (0.60 g, 4.4 mmol) sodium cyano borohydride (0.19 g, 2.9 mmol) were added and The reaction mixture was allowed to stir at 60 ° C overnight. After cooling, the reaction mixture was concentrated under vacuum and the residue was purified using scintillation chromatography (SiO 2; eluent: dichloromethane / methanol gradient) to give a white solid (0.007 g, 2%); MS (ISP): 286.0 ([37 Cl M + H] +), 284.0 ([35 Cl Μ + Η] +). Example 61

(1 H -imidazol-2-ylmethylH3-phenoxy-phenyl) -amine

/ = \

The title compound, MS (ISP): 266.2 ([M + H] +) was obtained in comparable yield as analogous to the procedure described for Example 11 using 3-phenoxyaniline in place of 2-isopropyl-6-methyl. -aniline. Example 62

(3-Benzyloxy-phenylH 1 H -imidazol-2-ylmethyl) -amine

HK ^ N

Hn

THE

The title compound, MS (ISP): 280.2 ([M + Hf)] was obtained in comparable yield as analogous to the procedure described for Example 11 using 3-benzyloxy aniline in place of 2-isopropyl-6-methylaniline. . Example 63

(4-Benzyloxy-phenylH1H-imidazol-2-ylmethyl) -amine

The title compound, MS (ISP): 280.0 ([M + H] +) was obtained from a

Comparable yield analogous to the procedure described for Example 11 using 4-benzyloxy aniline in place of 2-isopropyl-6-methylaniline. Example 64

(4-Chloro-3-methoxy-phenyl) - (1H-imidazol-2-ylmethyl) -amine

)

The title compound, MS (ISP): 240.2 ([37 Cl M + H] +), 238.0 ([35 Cl M + H] +) was obtained in comparable yield analogous to the procedure described for Example 11 with the use of 4-chloro-3-methoxyaniline in place of 2-isopropyl-6-methylaniline. Example 65

Ethyl- (1H-imidazol-2-ylmethyl) - (3-phenoxy-phenyl) -amine

f = \

HN ^ N

The title compound, MS (ISP): 294.2 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 12 step b) using (1H-imidazol-2-ylmethyl) - (3-phenoxy-phenyl) -amine (Example 61) in (1 H -imidazol-2-ylmethyl) - (3-fluoro-phenyl) -amine. Example 66

(3-Benzyloxy-phenyl-ethyl- (1H-imidazol-2-ylmethyl) -amine

HNx ^ N

The title compound, MS (ISP): 308.4 ((M + H) +) was obtained from a

comparable yield analogous to the procedure described for Example 12 step b) using (3-benzyloxy-phenyl) - (1H-imidazol-2-ylmethyl) -amine (Example 62) in Yugarda (1H-imidazol-2- ylmethyl) - (3-fluoro-phenyl) -amine. Example 67

(4-benzyloxy-phenyl) -ethyl- (1H-imidazol-2-ylmethyl) -amine

The title compound, MS (ISP): 308.3 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 12 step b) using (4-benzyloxy-phenyl) - ( 1H-imidazol-2-ylmethyl) -amine (Example 63) in Uruguay (1H-imidazol-2-ylmethyl) - (3-fluoro-phenyl) -amine. Example 68

(3,4-dichloro-phenyl) -ethyl- (1H-imidazol-2-ylmethyl) -amine

The title compound, MS (ISP): 2721 ([37 Cl M + H] +), 2702 ([35 Cl M + H] +) was obtained in comparable yield analogous to the procedure described for Example 12 using 3,4-dichloroaniline in place of 3-fluoraniline in step a) and using (3,4-dichloro-phenyl) - (1H-imidazol-2-ylmethyl) -amine in place of (1 H-imidazole -2-ylmethyl) - (3-fluoro-phenyl) -amine in step b. Example 69

(4-Chloro-3-methoxy-phenylH-1 H -imidazol-2-ylmethyl) -methyl-amine 4-Chloro-3-methoxy-phenyl) - (1H-imidazol-2-ylmethyl) -amine (0.10 g, 0.4 mmol) (Example 64) was dissolved in acetonitrile (4 mL). Then formaldehyde (0.08 ml, 1.1 mmol, 37% aqueous solution) and sodium cyanoboroidrate (0.08 g, 1.3 mmol) were added and the reaction mixture was allowed to stir at room temperature. environment overnight. The reaction mixture was concentrated under vacuum and the residue was purified using scintillation chromatography (SiO 2; eluent: methanol / dichloromethane gradient) to give a white solid (0.006 g, 6%); MS (ISP): 252.1 ([37 Cl M + Hf), 250.2 ([35 Cl M + Hf)). Example 70

(4-chloro-3-methoxy-phenylH1H-imidazol-2-ylmethyl) -isopropyl-amine

/ = \

Cl

The title compound, MS (ISP): 282.1 ([37 Cl M + Hf), 280.2 ([35 Cl M + Hf)) was obtained in comparable yield analogous to the procedure described for Example 1 step b) with a use of (4-chloro-3-methoxyphenyl) - (1H-imidazol-2-ylmethyl) -amine (Example 64) in place of (1H-imidazol-2-ylmethyl) -phenylamine. Example 71

(3-Bromo-phenyl-1H-imidazol-2-ylmethyl) -amine

r = \

The title compound, MS (ISP): 251.9; 254.1 ((M + Hf)) was obtained in comparable yield analogous to the procedure described for Example 11 using 3-bromo aniline in place of 2-isopropyl-6-methyl aniline.

(1 H -imidazol-2-ylmethyl) - (4-methoxy-phenyl) -amine

r = \

HN. / M

X

NH

The title compound, MS (ISP): 203.9 ((M + H) +) was obtained from a

Comparable yield analogous to the procedure described for Example 11 using 4-methoxy aniline in place of 2-isopropyl-6-methyl aniline. Example 73

(3,4-difluoro-phenylH1H-imidazol-2-ylmethyl) -amine

Comparable yield analogous to the procedure described for Example 11 using 3,4-difluoraniline in place of 2-isopropyl-6-methylaniline. Example 74

(3-chloro-4-fluoro-phenyl) - (1H-imidazol-2-ylmethyl-D-amine

Γ = \

F

The title compound, MS (ISP): 209.9 ((M + H) +) was obtained from a

f = \

Cl

F

15

The title compound, MS (ISP): 228.1 ([37 Cl M + H] +), 226.1 ([35 Cl M + H] +) was obtained in comparable yield analogous to the procedure described for Example 11 with the use of 3-chloro-4-fluoraniline in the place of 2-isopropyl-6-methylaniline. Example 75

(3-bromo-phenylH1H-imidazol-2-ylmethyl) -isopropylamine

The title compound, MS (ISP): 296.1; 294.1 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 1 using 3-bromo aniline in place of aniline in step a).

Example 76

(1H-Imidazol-2-ylmethyl) -isopropyl- (4-methoxy-phenyl) -amine

/ = \

The title compound, MS (ISP): 246.2 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 1 using 4-methoxy aniline in place of aniline in step a). Example 77

(3,4-Difluoro-phenylH-1 H -imidazol-2-ylmethyl) -isopropyl-amine

F

The title compound, MS (ISP): 252.1 ((M + H) +) was obtained in comparable yield as the procedure described for Example 1 using 3,4-difluoro aniline in place of aniline in step a. ). Example 78

(3-chloro-4-fluoro-phenylH1H-imidazol-2-ylmethyl) -isopropyl-amine

/ = \

The title compound, MS (ISP): 268.1; 270.1 ((IVHH) +) was obtained

in a comparable yield analogous to the procedure described for Example 1 using 3-chloro-4-fluorine aniline in place of aniline in step a). Example 79

(3-bromo-phenyl) -ethyl (1 H -imidazol-2-ylmethyl) -amine

The title compound, MS (ISP): 279.9; 281.9 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 1 using 3-bromo aniline in place of aniline in step a).

Example 80

Ethyl- (1H-imidazol-2-ylmethyl) - (4-methoxy-phenyl) -amine The title compound, MS (ISP): 231.9 ((M + H) +) was obtained in analogous comparable yield. to the procedure described for Example 12 using 4-methoxy aniline in place of 3-fluorine aniline in step a).

Example 81

(3,4-Difluoro-phenyl) -ethyl- (1H-imidazol-2-ylmethyl) -amine

HN N

The title compound, MS (ISP): 237m9 ((M + H) +) was obtained in comparable yield as analogous to the procedure described for Example 12 using 3,4-difluoro aniline instead. 3-fluorine aniline in step a). Example 82

(3-chloro-4-fluoro-phenyl) -ethyl- (1H-imidazol-2-ylmethyl) -amine

The title compound, MS (ISP): 253.9; 255.8 ((M + H) +) was obtained in comparable yield analogous to the procedure described for Example 12 with the use of 3-chloro-4-fluorine aniline in place of 3-fluorine aniline. in step a). Example 83

2-R-Biphenyl-3-yl- (1H-imidazol-2-ylmethyl) -amino-1-ethanol r = \

The title compound, MS (ISP): 294.1 ((M + H) +) was obtained in comparable yield as analogous to the procedure described for Example 2 using 2- (biphenyl-3-ylamino) -ethanol in place of 3-chloro-N-methylaniline.

Claims (16)

1. Compounds of formula I wherein R1 is hydrogen or C1.7 alkyl; R 2 is hydrogen, C 1-7 alkyl, C 1-7 alkenyl, C 1-7 hydroxy substituted alkyl, C 1-7 halogen substituted alkyl; - (CH2) xS-C1-7 alkyl, - (CH2) xO-C1.7 alkyl, - (CH2) x-NHC (O) O-C1-7 alkyl, - (CH2) x-aryl or - (CH2 ) x-heteroaryl; is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, hydroxy, C1-7 alkyl substituted by halogen; -0- (CH 2) m -aryl, -0- (CH 2) m -heteroaryl, - (CR 2) m -aryl or - (CR 2) m -heteroaryl; R is hydrogen, C1-7 alkyl, or hydroxy; Ar is phenyl, pyrimidin-2-yl, pyrimidin-4-yl or pyridin-3-yl; η is 0, 1, or 2; when η is 2, then the two groups R3 may or may not be the same; χ is O, 1,2 or 3; m is 0 or 1; when m is 1, then the two groups R may or may not be the same; and their pharmaceutically active salts, with the exception of the following known compounds: benzyl (1H-imidazol-2-ylmethyl) -phenylamine and ethyl (1H-imidazol-2-ylmethyl) -phenylamine. 2. Compounds of formula IA in which <formula> formula see original document page 59 </formula> wherein R1 is hydrogen C1-7 alkyl; R2 is hydrogen, C1-7 alkyl, C1-7 alkenyl, hydroxy substituted C1-7 alkyl, halogen substituted C1-7 alkyl; - (CH2) xS-C1-T alkyl, - (CH2) xO-C1-7 alkyl, - (CH2) x-NHC (O) O-C1-7 alkyl, - (CH2) x-aryl or - (CH2 ) x-heteroaryl; R3 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, hydroxy, C1-7 halogen substituted alkyl; -0- (CH 2) m -aryl, -0- (CH 2) m -heteroaryl, - (CR 2) m -aryl or - (CR 2) m -heteroaryl; R is hydrogen, C1-7 alkyl or hydroxy; X / X 'are independently CH or N, where XeX' are not simultaneously N; η is 0, 1 or 2; when η is 2, then the two groups R3 may or may not be the same; χ is O, 1,2 or 3; m is 0 or 1; when m is 1, then the two groups R may or may not be the same; and their pharmaceutically active salts, with the exception of the following known compounds: benzyl (1H-imidazol-2-ylmethyl) -phenylamine and ethyl (1H-imidazol-2-ylmethyl) -phenylamine. 3. Compounds of formula I wherein Ar is phenyl. Compounds of formula I according to claim 3 wherein R2 is C1-7 alkyl. Compounds of formula I according to claim 4, which compounds are: (3-chloro-phenyl) - (1H-imidazol-2-ylmethyl) -methylamine (4-chloro-phenyl) - ( 1H-imidazol-2-ylmethyl) methyl-amine (1H-imidazol-2-ylmethyl) - (3-methoxy-phenyl) -methyl-amine (4-fluorophenyl) - (1H-imidazole-2 Ethyl (3-fluorophenyl) - (1H-imidazol-2-ylmethyl) -amine (3-chloro-phenyl) - (1H-imidazol-2-ylmethyl) -isopropyl-ethyl (3-Chloro-phenyl) -ethyl- (1H-imidazol-2-ylmethyl) -amine (2,5-difluorophenyl) - (3H-imidazol-4-ylmethyl) -isopropyl-amine (1 H- imidazol-2-ylmethyl) -isopropyl-m-tolylamine (3-benzyloxy-phenyl) - (1H-imidazol-2-ylmethyl) -isopropyl-amine (1H-imidazol-2-ylmethyl) -isopropyl- [3 - (pyridin-3-yloxy) -phenyl] -amine (3-benzyl-phenyl) - (1H-imidazol-2-ylmethyl) -isopropyl-amine biphenyl-3-yl- (1H-imidazol-2-ylmethyl ) -isopropylamine [3- (4-chloro-phenoxy) -phenyl] - (1H-imidazol-2-ylmethyl) -isopropyl-amine Ethyl- (1H-imidazol-2-ylmethyl) - (3-phenoxy) phenyl) -amine (3-benzyloxy-phenyl) -ethyl- (1H-imidazole) 2-ylmethyl) -amine or (3,4-dichloro-phenyl) -ethyl- (1H-imidazol-2-ylmethyl) -amine. Compounds of formula I according to claim 3, wherein R2 is -CH2) x-O-C1-7 alkyl. Compounds of formula I according to claim 6, which compound is: (1H-imidazol-2-ylmethyl) - (2-methoxy-ethyl) -phenylamine. Compounds of formula I according to claim 1 wherein Ar is pyrimidin-2-yl. Compounds of formula I according to claim 1 wherein Ar is pyrimidin-4-yl. Compounds of formula I according to claim 1 wherein Ar is pyridin-3-yl. A process for the preparation of the compounds of formula I, the process of which comprises: (a) reacting a compound of the formula with a compound of the formula formula see original document </formula> III for a compound of the formula <formula> formula see original document page 61 </formula> wherein R11 R2, R3 η and Ar are as defined above, or (b) by reacting a compound of the formula <formula> > formula see original document page 61 </formula> with a compound of formula R2 -CHO for a compound of formula <formula> formula see original document page 62 </formula> in which R2e is lower alkyl, hydroxy lower alkenyl, substituted lower alkyl with halogen, - (CH 2) x 1 -S lower alkyl, - (CH 2) x I -O lower alkyl, (CH 2) x -RNHC (0) 0-lower alkyl or (CH 2) x I -heteroaryl and the other substituents are as defined above, or (c) by reacting a compound of the formula <formula> formula see original where the substituents are with, as defined above, or (d) removing a compound protecting group from the formula for a compound of the formula <formula> formula see original document page 63 </formula> wherein the substituents are as defined above, or (e) reducing a compound of the formula <formula> formula see original document page 63 </formula> VII to a compound of the formula <formula> formula see original document page 63 </formula> VIII and removing the protecting group for a compound of the formula in which substituents are defined above, or (f) reacting a compound of the formula <formula> formula see original document page 63 </formula> XII with a compound of the formula <formula> formula see original document page 63 </formula> XI for a compound of the formula <formula> formula see original document page 64 </formula> in which the substituents are defined above , and if desired by converting the compounds obtained into pharmaceutically acceptable acid addition salts. A compound according to claim 1, where it is prepared by a process as claimed in claim 11 or by an equivalent method. Medicament containing one or more compounds of formula I and the benzyl (1H-imidazol-2-ylmethyl) -phenylamine and ethyl (1H-imidazol-2-ylmethyl) -phenylamine compounds according to claim 1 , and pharmaceutically acceptable excipients. A medicament as claimed in claim 13 for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress related disorders, psychotic disorders such as schizophrenia, neurological disorders such as such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, drinking disorders and assimilation. energy, disorders and malfunction of body temperature homeostasis, sleep disorders and circadian rhythm and cardiovascular disorders. A medicament according to claim 14 containing one or more compounds as claimed in claim 1 for treating depression, psychosis, Parkinson's disease, anxiety and attention deficit hyperactivity disorder (ADHD). 16. Use of a compound of formula I and benzyl (1H-imidazol-2-ylmethyl) -phenylamine and ethyl (1H-imidazol-2-ylmethyl) -phenylamine compounds according to claim 1 for the preparation of a medicament for the treatment of depression, anxiety disorders, bipolar disorders, attention deficit hyperactivity disorder (ADHD), stress related disorders, psychotic disorders such as schizophrenia, neurological disorders such as such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, sleep disorders and circadian rhythm, and cardiovascular disorders.